Search

Benzalkonium chlorides (BACs) are commonly used disinfectants in a variety of consumer and food-processing settings, and the COVID-19 pandemic has led to increased usage of BACs. The prevalence of BACs raises the concern that BAC exposure could disrupt the gastrointestinal microbiota, thus interfering with the beneficial functions of the microbes. We hypothesize that BAC exposure can alter the gut microbiome diversity and composition, which will disrupt bile acid homeostasis along the gut-liver axis. In this study, male and female mice were exposed orally to d7-C12- and d7-C16-BACs at 120 µg/g/day for one week. UPLC-MS/MS analysis of liver, blood, and fecal samples of BAC-treated mice demonstrated the absorption and metabolism of BACs. Both parent BACs and their metabolites were detected in all exposed samples. Additionally, 16S rRNA sequencing was carried out on the bacterial DNA isolated from the cecum intestinal content. For female mice, and to a lesser extent in males, we found that treatment with either d7-C12- or d7-C16-BAC led to decreased alpha diversity and differential composition of gut bacteria with notably decreased actinobacteria phylum. Lastly, through a targeted bile acid quantitation analysis, we observed decreases in secondary bile acids in BAC-treated mice, which was more pronounced in the female mice. This finding is supported by decreases in bacteria known to metabolize primary bile acids into secondary bile acids, such as the families of Ruminococcaceae and Lachnospiraceae. Together, these data signify the potential impact of BACs on human health through disturbance of the gut microbiome and gut-liver interactions., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Society of Toxicology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Purpose: To compare the macular and optic disc vascular parameters in the unaffected fellow eyes of subjects with unilateral pseudoexfoliation syndrome (PXS) and controls using optical coherence tomography angiography (OCTA)., Methods: The medical records of 61 eyes of 61 patients were analyzed in a retrospective study. Of these, 30 eyes were unaffected fellow eyes and 31 eyes were control eyes. The vessel density (VD), perfusion density (PD) and foveal avascular zone (FAZ)-related parameters of the superficial capillary plexus (SCP) in the circumpapillary and macular area and the VD and PD of the deep capillary plexus (DCP) in the macular area were measured using OCTA after dilatation and were compared between two groups after adjustment for age, sex and axial length., Results: There were no statistically significant differences in sex ratio or mean age, central corneal thickness measurements, refractive errors, intraocular pressures and axial length between both groups (all P > 0.05). In the circumpapillary area, inferior VD and PD in the inner zone, as well as average, temporal, inferior, and nasal VD and PD in the outer zone were significantly reduced in the unaffected fellow eyes with unilateral PXS, while the circumpapillary retinal nerve fiber layer (RNFL) thicknesses were similar between groups. In the macular SCP, VDs were significantly lower in all sectors in the inner area and in the outer zones (p < 0.05 for all), PDs were significantly lower in all sectors (p < 0.05 for all) except the nasal sector of the outer zone (p = 0.003 for average, p = 0.029 for superior sector, p = 0.004 for temporal sector, p < 0.001 for inferior sector), and the FAZ circularity (p = 0.037) were significantly lower in the unaffected fellow eyes with unilateral PXS, whereas macular ganglion cell inner plexiform layer (GCIPL) thickness was similar between the two groups., Conclusions: Although circumpapillary RNFL and GCIPL thicknesses were similar between the two groups, VDs and PDs in the circumpapillary and macular SCP and FAZ circularity were significantly lower in the fellow eye of subjects with unilateral PXS., (© 2024. The Author(s).)

Muscle-specific kinase (MuSK) is essential for the formation, function, and preservation of neuromuscular synapses. Activation of MuSK by a MuSK agonist antibody may stabilize or improve the function of the neuromuscular junction (NMJ) in patients with disorders of the NMJ, such as congenital myasthenia (CM). Here, we generated and characterized ARGX-119, a first-in-class humanized agonist monoclonal antibody specific for MuSK, that is being developed for treatment of patients with neuromuscular diseases. We performed in vitro ligand-binding assays to show that ARGX-119 binds with high affinity to the Frizzled-like domain of human, nonhuman primate, rat, and mouse MuSK, without off-target binding, making it suitable for clinical development. Within the Fc region, ARGX-119 harbors L234A and L235A mutations to diminish potential immune-activating effector functions. Its mode of action is to activate MuSK, without interfering with its natural ligand neural Agrin, and cluster acetylcholine receptors in a dose-dependent manner, thereby stabilizing neuromuscular function. In a mouse model of DOK7 CM, ARGX-119 prevented early postnatal lethality and reversed disease relapse in adult Dok7 CM mice by restoring neuromuscular function and reducing muscle weakness and fatigability in a dose-dependent manner. Pharmacokinetic studies in nonhuman primates, rats, and mice revealed a nonlinear PK behavior of ARGX-119, indicative of target-mediated drug disposition and in vivo target engagement. On the basis of this proof-of-concept study, ARGX-119 has the potential to alleviate neuromuscular diseases hallmarked by impaired neuromuscular synaptic function, warranting further clinical development.

Purpose: To represent 24-2 visual field (VF) losses of individual patients using a hybrid approach of archetypal analysis (AA) and fuzzy c-means (FCM) clustering., Methods: In this multicenter retrospective study, we classified characteristic patterns of 24-2 VF using AA and decomposed them with FCM clustering. We predicted the change in mean deviation (MD) through supervised machine learning from decomposition coefficient change. In addition, we compared the areas under the receiver operating characteristic curves (AUCs) of the decomposition coefficient slopes to detect VF progression using three criteria: MD slope, Visual Field Index slope, and pointwise linear regression analysis., Results: We identified 16 characteristic patterns (archetypes or ATs) of 24-2 VF from 132,938 VFs of 18,033 participants using AA. The hybrid approach using FCM revealed a lower mean squared error and greater correlation coefficient than the AA single approach for predicting MD change (all P ≤ 0.001). Three of 16 AUCs of the FCM decomposition coefficient slopes outperformed the AA decomposition coefficient slopes in detecting VF progression for all three criteria (AT5, superior altitudinal defect; AT10, double arcuate defect; AT13, total loss) (all P ≤ 0.028)., Conclusion: A hybrid approach combining AA and FCM to analyze 24-2 VF can visualize VF tests in characteristic patterns and enhance detection of VF progression with lossless decomposition., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Kim et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Background: Progressive supranuclear palsy (PSP) is largely a sporadic disease with few reported familial cases. Genome-wide association studies (GWAS) in sporadic PSP in Caucasian populations have identified MAPT as the most commonly associated genetic risk locus with the strongest effect size. At present there are limited data on genetic factors associated with PSP in Asian populations., Objectives: Our goal was to investigate the genetic factors associated with PSP in Southeast Asian PSP patients., Methods: Next-generation sequencing (whole-exome, whole-genome and targeted sequencing) was performed in two Asian cohorts, comprising 177 PSP patients., Results: We identified 17 pathogenic or likely pathogenic variants in 16 PSP patients (9%), eight of which were novel. The most common relevant genetic variants identified were in MAPT, GBA1, OPTN, SYNJ1, and SQSTM1. Other variants detected were in TBK1, PRNP, and ABCA7-genes that have been implicated in other neurodegenerative diseases. Eighteen patients had a positive family history, of whom two carried pathogenic MAPT variants, and one carried a likely pathogenic GBA1 variant. None of the patients had expanded repeats in C9orf72. Furthermore, we found 16 different variants of uncertain significance in 21 PSP patients in PSEN2, ABCA7, SMPD1, MAPT, ATP13A2, OPTN, SQSTM1, CYLD, and BSN., Conclusions: The genetic findings in our PSP cohorts appear to be somewhat distinct from those in Western populations, and also suggest an overlap of the genetic architecture between PSP and other neurodegenerative diseases. Further functional studies and validation in independent Asian cohorts will be useful for improving our understanding of PSP genetics and guiding genetic screening strategies in these populations. © 2024 International Parkinson and Movement Disorder Society., (© 2024 International Parkinson and Movement Disorder Society.)

CD73 is a cell-surface ectoenzyme that hydrolyzes the conversion of extracellular adenosine monophosphate to adenosine, which in turn can promote resistance to immune checkpoint blockade therapy. Immune response may therefore be improved by targeting tumor CD73, and this possibility underlines the need to non-invasively assess tumor CD73 level. In this study, we developed a cysteine site-specific 89 Zr-labeled anti-CD73 ( 89 Zr-CD73) IgG immuno-PET technique that can image tumor CD73 expression in living bodies. Anti-CD73 IgG was reduced with tris(2-carboxyethyl)phosphine, underwent sulfohydryl moiety-specific conjugation with deferoxamine-maleimide, and was radiolabeled with 89 Zr. CT26 mouse colon cancer cells, CT26/CD73 cells engineered to constitutively overexpress CD73, and 4T1.2 mouse breast cancer cells underwent cell binding assays and western blotting. Balb/c nude mice bearing tumors underwent 89 Zr-CD73 IgG PET imaging and biodistribution studies. 89 Zr-CD73 IgG showed 20-fold higher binding to overexpressing CT26/CD73 cells compared to low-expressing CT26 cells, and moderate expressing 4T1.2 cells showed uptake that was 38.9 ± 1.51% of CT26/CD73 cells. Uptake was dramatically suppressed by excess unlabeled antibody. CD73 content proportionately increased in CT26 and CT26/CD73 cell mixtures was associated with linear increases in 89 Zr-CD73 IgG uptake. 89 Zr-CD73 IgG PET/CT displayed clear accumulation in CT26/CD73 tumors with greater uptake compared to CT26 tumors (3.13 ± 1.70%ID/g vs. 1.27 ± 0.31%ID/g at 8 days; P = 0.04). Specificity was further supported by low CT26/CD73 tumor-to-blood ratio of 89 Zr-isotype-IgG compared to 89 Zr-CD73 IgG (0.48 ± 0.08 vs. 2.68 ± 0.52 at 4 days and 0.53 ± 0.07 vs. 4.81 ± 1.02 at 8 days; both P < 0.001). Immunoblotting and immunohistochemistry confirmed strong CD73 expression in CT26/CD73 tumors and low expression in CT26 tumors. 4T1.2 tumor mice also showed clear 89 Zr-CD73 IgG accumulation at 8 days (3.75 ± 0.70%ID/g) with high tumor-to-blood ratio compared to 89 Zr-isotype-IgG (4.91 ± 1.74 vs. 1.20 ± 0.28; P < 0.005). 89 Zr-CD73 IgG specifically targeted CD73 on high expressing cancer cells in vitro and tumors in vivo. Thus, 89 Zr-CD73 IgG immuno-PET may be useful for the non-invasive monitoring of CD73 expression in tumors of living subjects., (© 2024. The Author(s).)

Background: Screening for orthostatic hypotension (OH) is integral in Parkinson's disease (PD) management, yet evidence-based guidelines on best practice methods for diagnosing OH in PD are lacking., Methods: We investigated the frequency and correlates of OH, symptomatic OH, and neurogenic OH, in a large consecutively recruited PD cohort (n = 318), and compared the diagnostic performance of the sit-to-stand vs. the supine-to-stand blood pressure (BP) test. We evaluated the utility of continuous BP monitoring and tilt table testing in patients with postural symptoms or falls who were undetected to have OH with clinic-based BP measurements. Disease severity, fluid intake, orthostatic and overactive bladder symptoms, falls, comorbidities and medication history were evaluated., Results: Patients' mean age was 66.1 ± 9.5years, with mean disease duration 7.8 ± 5.5years. OH frequency was 35.8 % based on the supine-to-stand test. OH in PD was significantly associated with older age, lower body mass index, longer disease duration, worse motor, cognitive and overactive bladder symptoms and functional disabilities, falls, and lower fluid intake. A similar profile was seen with asymptomatic OH. Three quarters of OH were neurogenic, with the majority also having supine hypertension. The sit-to-stand test had a sensitivity of only 0.39. One quarter of patients were additionally diagnosed with OH during continuous BP monitoring., Conclusions: The sit-to-stand test substantially underdiagnoses OH in PD, with the important practice implication that supine-to-stand measurements may be preferred. Screening for OH is warranted even in asymptomatic patients. Adequate fluid intake, treatment of urinary dysfunction and falls prevention are important strategies in managing PD patients with OH., Competing Interests: Declaration of competing interest None., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Purpose: Penicillin allergy is the most common drug allergy among hospitalized patients. Traditionally, aztreonam is recommended for patients labeled with penicillin allergy (PLWPA) in our institutional empirical antibiotic guidelines. Due to a global aztreonam shortage in December 2022, the antimicrobial stewardship unit recommended ceftazidime as a substitute. There is a paucity of real-world data on the safety profile of ceftazidime in PLWPA. Hence, we evaluated tolerability outcomes of ceftazidime use in PLWPA., Methods: This retrospective cohort study compared PLWPA in Singapore General Hospital who received aztreonam (October 2022-December 2022) or ceftazidime (December 2022-February 2023). Patients were stratified according to their risk of allergic reaction (AR) based on history of penicillin allergy. The severity of AR was based on the Delphi study grading system. The primary outcome was development of AR after initiation of aztreonam or ceftazidime. The secondary tolerability outcomes include hepatotoxicity and neurotoxicity., Findings: There were 168 patients in the study; 69 were men (41.1%) and the median age was 69 years (interquartile range: 59-76 years). Incidence of AR was statistically similar in both arms: 1 of 102 patients (0.98%) in the aztreonam arm vs 2 of 66 patients (3.03%) in the ceftazidime arm (P = 0.33). The patient in the aztreonam arm was deemed at medium risk of having an AR and developed localized rashes (grade 1). Both patients in the ceftazidime arm were deemed at high risk of AR and developed localized skin reaction (grade 1). Hepatotoxicity was observed in 1 patient prescribed aztreonam. No patients in the ceftazidime arm developed adverse events., Implications: Ceftazidime appears to be better tolerated and cheaper compared with aztreonam in PLWPA, and serves as an antimicrobial stewardship strategy to conserve broader-spectrum antibiotics use., Competing Interests: Declaration of competing interest None., (Copyright © 2024 Elsevier Inc. All rights reserved.)

This study investigated exercise participation, health status, and barriers to exercise in 109 individuals with spinal cord injury (SCI) using a self-report questionnaire. The responses of the exercise and non-exercise groups were statistically analyzed using t-tests or Fisher's exact test. Significant differences were observed in the cause of injury and the American Spinal Injury Association Impairment Scale between the groups. The non-exercise group had a higher incidence of traumatic and complete injuries. Demographic factors such as gender, age, income level, and marital status did not significantly influence exercise participation. The exercise group reported lower pain scores, less inconvenience from complications, and higher activity and participation scores. However, less than half of the individuals with SCI met the recommended exercise intensity, and community facility usage was low. Barriers to exercise participation included severe disabilities, lack of time, insufficient exercise information, and lack of facility accessibility. To enhance exercise among individuals with SCI, it is essential to develop and extend exercise programs tailored to individual physical factors and a comprehensive understanding of barriers. Prioritizing community-based data management, alongside developing social systems and health policies, is crucial to overcome barriers to exercise participation for individuals with SCI.

The production of lentiviral vectors (LVs) pseudotyped with the vesicular stomatitis virus envelope glycoprotein (VSV-G) is limited by the associated cytotoxicity of the envelope and by the production methods used, such as transient transfection of adherent cell lines. In this study, we established stable suspension producer cell lines for scalable and serum-free LV production derived from two stable, inducible packaging cell lines, named GPRG and GPRTG. The established polyclonal producer cell lines produce self-inactivating (SIN) LVs carrying a WAS-T2A-GFP construct at an average infectious titer of up to 4.64 × 10 7  TU mL -1  in a semi-perfusion process in a shake flask and can be generated in less than two months. The derived monoclonal cell lines are functionally stable in continuous culture and produce an average infectious titer of up to 9.38 × 10 7  TU mL -1  in a semi-perfusion shake flask process. The producer clones are able to maintain a productivity of >1 × 10 7  TU mL -1  day -1  for up to 29 consecutive days in a non-optimized 5 L stirred-tank bioreactor perfusion process, representing a major milestone in the field of LV manufacturing. As the producer cell lines are based on an inducible Tet-off expression system, the established process allows LV production in the absence of inducers such as antibiotics. The purified LVs efficiently transduce human CD34 + cells, reducing the LV quantities required for gene and cell therapy applications., (© 2024 CSL Innovation GmbH and The Authors. Biotechnology Journal published by Wiley‐VCH GmbH.)

This study aimed to examine the physical activity and exercise status of stroke patients in the community after discharge and the need for community-based exercises. This study included 100 community-dwelling patients with stroke in South Korea. The survey investigated the self-assessment of health status and physical activity, demand for community-based exercise after discharge, quality of life, and social participation. Overall, 96% of the respondents recognized the need to exercise, and two-thirds exercised. The third who did not exercise cited disability (29%), lack of facilities (22%), and health concerns (13%); only 21% of participants had ever used a community exercise facility, and their satisfaction with the facility was low. The main reasons for not using community exercise facilities were concerns about accidents during exercise and accessibility issues. Among real-world community stroke patients, those who exercised regularly had higher EuroQol-5D and reintegration to normal living indices than those who did not exercise ( p < 0.05). Although community-dwelling stroke patients were highly aware of the need for physical activity and exercise, few engaged in adequate exercise. This lack of engagement is directly linked to identifiable personal and socio-structural barriers. Addressing these barriers will improve the quality of life and social participation of patients with stroke.

Very late antigen-4 (VLA4; CD49d) is a promising immune therapy target in treatment-resistant leukemia and multiple myeloma, and there is growing interest in repurposing the humanized monoclonal antibody (Ab), natalizumab, for this purpose. Positron emission tomography with radiolabeled Abs (immuno-PET) could facilitate this effort by providing information on natalizumab's in vivo pharmacokinetic and target delivery properties. In this study, we labeled natalizumab with 89 Zr specifically on sulfhydryl moieties via maleimide-deferoxamine conjugation. High VLA4-expressing MOLT4 human T cell acute lymphoblastic leukemia cells showed specific 89 Zr-natalizumab binding that was markedly blocked by excess Ab. In nude mice bearing MOLT4 tumors, 89 Zr-natalizumab PET showed high-contrast tumor uptake at 7 days postinjection. Biodistribution studies confirmed that uptake was the highest in MOLT4 tumors (2.22 ± 0.41%ID/g) and the liver (2.33 ± 0.76%ID/g), followed by the spleen (1.51 ± 0.42%ID/g), while blood activity was lower at 1.12 ± 0.21%ID/g. VLA4-specific targeting in vivo was confirmed by a 58.1% suppression of tumor uptake (0.93 ± 0.15%ID/g) when excess Ab was injected 1 h earlier. In cultured MOLT4 cells, short-term 3 day exposure to the proteasome inhibitor bortezomib (BTZ) did not affect the α4 integrin level, but BTZ-resistant cells that survived the treatment showed increased α4 integrin expression. When the effects of BTZ treatment were tested in mice, there was no change of the α4 integrin level or 89 Zr-natalizumab uptake in MOLT4 leukemia tumors, which underscores the complexity of tumor VLA4 regulation in vivo. In conclusion, 89 Zr-natalizumab PET may be useful for noninvasive monitoring of tumor VLA4 and may assist in a more rational application of Ab-based therapies for hematologic malignancies.

Background: We aimed at evaluating the diagnostic performance of rapid antigen test (RAT) compared to polymerase chain reaction (PCR) for severe acute respiratory syndrome coronavirus 2 and the possible transmission of infection to close contacts from patients with negative RAT and positive PCR results., Materials and Methods: Patients/guardians urgently requiring admission to the ward on the same day had been hospitalized with RAT-negative result before the PCR results were available. We performed an epidemiologic investigation of the close contacts of those with negative RAT but positive PCR results after hospitalization., Results: A total of 4,237 RATs were performed from March to August 2022. When the PCR test was used as the reference, RAT had a sensitivity of 28.8% (17/59; 95% confidence interval [CI], 17.8 - 42.1), a specificity of 100% (4,220/4,220; 95% CI, 99.9 - 100.0), a positive predictive value of 100.0% (17/17; 95% CI, 100.0 - 100.0), and a negative predictive value of 99.0% (4,178/4,220; 95% CI, 99.3 - 99.8). The epidemiologic investigation revealed that among the 32 patients with negative RAT and subsequent positive PCR results after admission into multi-patient room, two (6.3%) showed secondary coronavirus disease 2019., Conclusion: The secondary transmission rate from patients with negative RAT and positive PCR results was low. Our data suggest that RAT may be useful for rapid exclusion of high transmissible cases. However, further evaluation using whole genome sequencing is needed to determine the potential for transmissibility in cases showing a negative RAT but a positive PCR result., Competing Interests: No conflict of interest., (Copyright © 2024 by The Korean Society of Infectious Diseases, Korean Society for Antimicrobial Therapy, and The Korean Society for AIDS.)

Background: Hepatitis B virus reactivation (HBVr) is a well-known complication of systemic chemotherapy for particularly hematologic malignancies in HBV carriers. We performed a multicenter retrospective study to investigate the incidence and risk factors of HBVr in patients with hepatitis B surface antigen (HBsAg)-positive multiple myeloma (MM)., Methods: We included 123 patients with HBsAg-positive MM who had received systemic therapy. The primary objective of the study was to evaluate the incidence of HBVr in patients with HBsAg-positive MM., Results: The median age was 59 years, and 72 patients were male. With a median follow-up duration of 41.4 months, there were 43 instances of HBVr in 35 patients (28.5%): 29 treatment-related HBVr occurred during 424 treatments. Treatments containing antiviral prophylaxis were associated with a significantly lower incidence of HBVr compared to those without (14.4% vs. 1.9%, P < 0.001). Moreover, treatment with cyclophosphamide (P = 0.002) and doxorubicin (P = 0.053) were risk factors for HBVr; stem cell transplantation was not associated with HBVr. There was no significant difference in overall survival between patients with and without HBVr (P = 0.753) and myeloma progression was the major cause of death., Conclusion: Considering the low incidence of HBVr in patients who had received antiviral prophylaxis, HBsAg-positivity should not impede patients from receiving optimal antimyeloma treatment or participating in clinical trials., Competing Interests: Disclosure The authors have stated that they have no conflicts of interest., (Copyright © 2023. Published by Elsevier Inc.)

Purpose: In the present study, we determined the prevalence of obstructive meibomian gland dysfunction (MGD), hyposecretory MGD, grossly normal MG, and hypersecretory MGD in patients with dry eye syndrome using lipid layer thickness (LLT) and MG dropout., Methods: Eighty-eight patients with dry eye syndrome were included in the study. Patients were categorized into four groups according to the LLT and weighted total meiboscore. The proportion of patients in each group was calculated. The age, sex, Ocular Surface Disease Index, LLT, Schirmer, tear film breakup time, cornea stain, weighted total meiboscore, expressibility, and quality of meibum were compared between the four groups., Results: Fifteen eyes (17.0%) had obstructive MGD, two eyes (2.3%) had hyposecretory MGD, 40 eyes (45.5%) had grossly normal MG, and 17 eyes (19.3%) had hypersecretory MGD. The obstructive MGD group was younger than the grossly normal MG group. In obstructive MGD, the ratio of men to women was higher than that of the other groups. However, Ocular Surface Disease Index, Schirmer, tear film breakup time, and corneal stain did not show statistically significant differences between the four groups. The meibum expressibility of the hyposecretoy MGD group was worse than those of the other groups. The meibum expressibility of the hyposecretoy MGD group was poor than those of the obstructive and hypersecretory MGD group., Conclusions: This categorization was expected to help determine the best treatment method for dry eye syndrome, according to the MG status.

The amyloid cascade and tau hypotheses both hold significant implications for the pathogenesis of Alzheimer's disease (AD). Curcumin shows potential by inhibiting the aggregation of amyloid beta (Aβ) and reducing tau hyperphosphorylation, however, its use is limited due to issues with solubility and bioavailability. Carbon dots, recognized for their high biocompatibility and optimal water solubility, have demonstrated the capability to inhibit either Aβ or tau aggregation. Nonetheless, their effects on tau hyperphosphorylation are yet to be extensively explored. This study aims to evaluate the water-soluble curcumin-derived carbon quantum dots (Cur-CQDs) synthesized via an eco-friendly method, designed to preserve the beneficial effects of curcumin while overcoming solubility challenges. The synthesis of Cur-CQDs involves a single-step dry heating process using curcumin, resulting in dots that exhibit negligible cytotoxicity to SH-SY5Y cells at the examined concentrations. Notably, Cur-CQDs have shown the ability to simultaneously mitigate Aβ aggregation and tau hyperphosphorylation. Therefore, it is suggested that Cur-CQDs may hold potential for AD treatment, a hypothesis deserving of further research., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier B.V. All rights reserved.)

There has been increasing interest in mobile healthcare for diabetes management. However, there remains limited evidence regarding the effectiveness of these mobile applications (apps). This scoping review aimed to evaluate the clinical effectiveness of mobile diabetes management apps. We used the following search terms: "mobile app", "mobile application", and "diabetes". We included only articles written in English and published between January 2016 and August 2021. We identified two, six, and four articles focused on type 1 diabetes, type 2 diabetes, and both diabetes types, respectively. Five, four, and three of these studies reported on the apps' functionality, usability, and both, respectively. Our findings indicated that diabetes mobile apps allowed for convenient user experience and improved blood sugar levels in patients with diabetes. Considering these findings, usability must be comprehensively evaluated by using definitions such as the ISO9241-11 usability definition or the mobile application rating scale (MARS) when developing diabetes-related apps. For the feasibility of diabetes mobile apps, we recommend that HbA1C and self-management be included as evaluation variables. Given the increasing importance of continuous management for patients with diabetes, interventions using mobile apps are bound to become effective tools for patient-led self-management.

RIP1 (receptor-interacting protein kinase 1) is an important component of TNF-α signaling that contributes to various pathological effects. Here, we revealed new potential roles of RIP1 in controlling WNT/β-catenin canonical signaling to enhance metastasis of colorectal cancer (CRC). First, we showed that WNT3A treatment sequentially increased the expression of RIP1 and β-catenin. Immunohistochemical analyses of human CRC tissue arrays consisting of normal, primary, and metastatic cancers indicated that elevated RIP1 expression might be related to β-catenin expression, carcinogenesis, and metastasis. Intravenous injection of RIP1 over-expressed CRC cells into mice has demonstrated that RIP1 may promote metastasis. Immunoprecipitation (IP) results indicated that WNT3A treatment induces direct binding between RIP1 and β-catenin, and that this stabilizes the β-catenin protein in a manner that depends on the regulation of RIP1 ubiquitination via downregulation of the E3 ligase, cIAP1/2. Elimination of cIAP1/2 expression and inhibition of its ubiquitinase activity enhance WNT3A-induced RIP1 and β-catenin protein expression and binding, which stimulates endothelial-mesenchymal transition (EMT) induction to enhance the migration and invasion of CRC cells in vitro. The results of the in vitro binding assay and IP of exogenous RIP1-containing CRC cells additionally verified the direct binding of RIP1 and β-catenin. RIP1 expression can destroy the β-catenin-β-TrCP complex. Taken together, these results suggest a novel EMT-enhancing role of RIP1 in the WNT pathway and suggest a new canonical WNT3A-RIP1-β-catenin pathway that contributes to CRC malignancy by promoting EMT., (© 2023. The Author(s).)

Background: Forest landscape restoration (FLR), often through tree planting, is one of the priorities in many global and national initiatives for carbon offsetting as part of climate change mitigation and biodiversity conservation. However, active efforts to meet FLR objectives entail substantial costs for the procurement of planting stocks and require an experienced workforce for planting and nurturing tree seedlings. Alternatively, restoration projects can be more cost-effective and potentially may have greater biodiversity gain through assisting and accelerating natural forest regeneration. The use of perches is one of the strategies under Assisted Natural Regeneration (ANR) and is used to attract avian seed dispersers to degraded habitats for increased tree seed supply and seedling establishment. This systematic review and potential meta-analysis aim to determine the effectiveness of artificial and natural perches in promoting natural forest regeneration. Specifically, we will evaluate their effectiveness in driving seed richness, seed density, seedling richness, and seedling density. The results will synthesize available evidence on the topic, identify knowledge gaps we need filling to upscale the strategy, and inform their use in concert with other ANR strategies., Methods: The search strategy was informed through a literature scan and discussions with stakeholders and experts. A total of eight databases, which include an organizational library and a web-based search engine, will be searched using the refined search string in English. The search string was formed using keywords corresponding to the PICO structure of the research question, and its comprehensiveness was evaluated using 10 benchmark articles. The search results will be screened by the review team (composed of a primary and at least two secondary reviewers) using the set eligibility criteria at the title and abstract level, followed by the full-text screening. The screened studies will then undergo critical appraisal using the assessment criteria based on risk of bias and methods. Data from the accepted studies will be extracted to the standard data sheet for meta-analysis. Effect size (Hedges' g) will be computed to determine whether perches are effective in increasing seed dispersal and seedling establishment in degraded sites. The effect of potential modifiers relating to the landscape will be explored via mixed models., (© 2023. The Author(s).)

Although deep learning architecture has been used to process sequential data, only a few studies have explored the usefulness of deep learning algorithms to detect glaucoma progression. Here, we proposed a bidirectional gated recurrent unit (Bi-GRU) algorithm to predict visual field loss. In total, 5413 eyes from 3321 patients were included in the training set, whereas 1272 eyes from 1272 patients were included in the test set. Data from five consecutive visual field examinations were used as input; the sixth visual field examinations were compared with predictions by the Bi-GRU. The performance of Bi-GRU was compared with the performances of conventional linear regression (LR) and long short-term memory (LSTM) algorithms. Overall prediction error was significantly lower for Bi-GRU than for LR and LSTM algorithms. In pointwise prediction, Bi-GRU showed the lowest prediction error among the three models in most test locations. Furthermore, Bi-GRU was the least affected model in terms of worsening reliability indices and glaucoma severity. Accurate prediction of visual field loss using the Bi-GRU algorithm may facilitate decision-making regarding the treatment of patients with glaucoma., (© 2023. The Author(s).)

Background: About 5-10% of Parkinson's disease (PD) cases are early onset (EOPD), with several genes implicated, including GBA1, PRKN, PINK1, and SNCA. The spectrum and frequency of mutations vary across populations and globally diverse studies are crucial to comprehensively understand the genetic architecture of PD. The ancestral diversity of Southeast Asians offers opportunities to uncover a rich PD genetics landscape, and identify common regional mutations and new pathogenic variants., Objectives: This study aimed to investigate the genetic architecture of EOPD in a multi-ethnic Malaysian cohort., Methods: 161 index patients with PD onset ≤50 years were recruited from multiple centers across Malaysia. A two-step approach to genetic testing was used, combining a next-generation sequencing-based PD gene panel and multiplex ligation-dependent probe amplification (MLPA)., Results: Thirty-five patients (21.7%) carried pathogenic or likely pathogenic variants involving (in decreasing order of frequency): GBA1, PRKN, PINK1, DJ-1, LRRK2, and ATP13A2. Pathogenic/likely pathogenic variants in GBA1 were identified in thirteen patients (8.1%), and were also commonly found in PRKN and PINK1 (11/161 = 6.8% and 6/161 = 3.7%, respectively). The overall detection rate was even higher in those with familial history (48.5%) or age of diagnosis ≤40 years (34.8%). PRKN exon 7 deletion and the PINK1 p.Leu347Pro variant appear to be common among Malay patients. Many novel variants were found across the PD-related genes., Conclusions: This study provides novel insights into the genetic architecture of EOPD in Southeast Asians, expands the genetic spectrum in PD-related genes, and highlights the importance of diversifying PD genetic research to include under-represented populations., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: SYL, KL and CK have received honoraria from the Global Parkinson's Genetics Project (GP2) funded by the Michael J. Fox Foundation (MJFF) and the Aligning Science Across Parkinson's (ASAP) initiative. PB and VS are employees, and AR the founder and CEO, of Centogene AG. The other authors (AHT, YWT, JLL, AAA, KAI, ZAA, YTC, ASM, TTL, IL, YKC, JCEO, WKC, AMFDC, LCL, JWH, TST and KAM) have no conflict of interest., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Background: Medication use typically involves physicians prescribing, pharmacists reviewing, and nurses administering medications to patients. Drug information (DI) is often required during the process, with the various health care professionals (HCPs) seeking information differently according to their needs and familiarity with various resources., Objective: This systematic literature review aims to evaluate studies on drug information-seeking behaviour (ISB) of physicians, nurses and pharmacists to ascertain their DI needs, DI sources used, facilitators and barriers to DI-seeking., Methods: A systematic search was conducted on PubMed, Embase.com, Scopus, PsycINFO, CINAHL and Cochrane Library to identify eligible primary research articles published between January 2000 and May 2020., Results: The reviewed studies (N = 48) revealed that HCPs have a wide range of DI needs, with the top needs being similar across the three HCPs. Information sources used most often by all three groups were tertiary, followed by human and primary sources. Factors relating to the source characteristics were the most reported facilitators and barriers to DI-seeking. Some differences in drug ISB were also identified., Conclusion: Our findings can also guide information providers and educators to optimize information provision. It may also facilitate effective communication amongst HCPs when obtaining DI from or providing DI to one another., (© 2023 Health Libraries Group.)

Muscle-specific kinase (MuSK) is crucial for acetylcholine receptor (AChR) clustering and thereby neuromuscular junction (NMJ) function. NMJ dysfunction is a hallmark of several neuromuscular diseases, including MuSK myasthenia gravis. Aiming to restore NMJ function, we generated several agonist monoclonal antibodies targeting the MuSK Ig-like 1 domain. These activated MuSK and induced AChR clustering in cultured myotubes. The most potent agonists partially rescued myasthenic effects of MuSK myasthenia gravis patient IgG autoantibodies in vitro. In an IgG4 passive transfer MuSK myasthenia model in NOD/SCID mice, MuSK agonists caused accelerated weight loss and no rescue of myasthenic features. The MuSK Ig-like 1 domain agonists unexpectedly caused sudden death in a large proportion of male C57BL/6 mice (but not female or NOD/SCID mice), likely caused by a urologic syndrome. In conclusion, these agonists rescued pathogenic effects in myasthenia models in vitro, but not in vivo. The sudden death in male mice of one of the tested mouse strains revealed an unexpected and unexplained role for MuSK outside skeletal muscle, thereby hampering further (pre-) clinical development of these clones. Future research should investigate whether other Ig-like 1 domain MuSK antibodies, binding different epitopes, do hold a safe therapeutic promise., (© 2023. The Author(s).)

This study aimed to explore research topic trends on turnover intention among Korean hospital nurses by analyzing the keywords and topics of related articles. Methods: This text-mining study collected, processed, and analyzed text data from 390 nursing articles published between 1 January 2010 and 30 June 2021 that were collected via search engines. The collected unstructured text data were preprocessed, and the NetMiner program was used to perform keyword analysis and topic modeling. Results: The word with the highest degree centrality was "job satisfaction", the word with the highest betweenness centrality was "job satisfaction", and the word with the highest closeness centrality and frequency was "job stress". The top 10 keywords in both the frequency analysis and the 3 centrality analyses included "job stress", "burnout", "organizational commitment", "emotional labor", "job", and "job embeddedness". The 676 preprocessed key words were categorized into five topics: "job", "burnout", "workplace bullying", "job stress", and "emotional labor". Since many individual-level factors have already been thoroughly investigated, future research should concentrate on enabling successful organizational interventions that extend beyond the microsystem.

This study attempted to illustrate whether mental health deterioration could be alleviated by high social capital in an environment with high economic inequality. Daily mental stress was employed as a mental health factor when analyzing the association with economic inequality in the Seoul Survey data. Regarding social capital, community trust and altruism were included as cognitive dimensions, and participation and cooperation were included as structural dimensions in each model. The first finding showed a significantly positive relationship between economic inequality and daily stress, meaning that, like other mental health problems, daily mental stress is also high in regions with high economic inequality. Second, the slope of the daily stress increased in respondents with high social trust and participation was alleviated in an economically unequal environment. This indicates that social trust and participation have a buffering effect by moderating the slope of daily stress in societies with high inequality. Third, the buffering effect differs depending on the social capital factor. The buffering effect of trust and participation showed in an unequal environment, while the buffering effect of cooperation showed regardless of the unequal environment. In summary, social capital factors showed the effect of relieving daily mental stress in the relationship with economic inequality. Also, the buffering effect of social capital on mental health may show different aspects for each element., (© 2023. The Author(s).)

Background: Progressive supranuclear palsy (PSP) is a rare, disabling, neurodegenerative disease, with few studies done in Asian populations., Methods: We prospectively characterized the clinical features and disease burden in a consecutively-recruited multi-ethnic Asian PSP cohort. Patients were extensively phenotyped using the Movement Disorder Society (MDS-PSP) clinical diagnostic criteria and the PSP-Clinical Deficits Scale (PSP-CDS). Caregiver burden was measured using the modified Zarit Burden Interview (ZBI). Investigations (neuroimaging and genetic tests) were reviewed., Results: There were 104 patients (64.4% male; 67.3% Chinese, 21.2% Indians, 9.6% Malays), consisting of 48.1% Richardson syndrome (PSP-RS), 37.5% parkinsonian phenotype (PSP-P), and 10.6% progressive gait freezing phenotype (PSP-PGF). Mean age at motor onset was 66.3 ± 7.7 years, with no significant differences between the PSP phenotypes. Interestingly, REM-sleep behaviour disorder (RBD) symptoms and visual hallucinations (considered rare in PSP) were reported in 23.5% and 22.8% of patients, respectively, and a family history of possible neurodegenerative or movement disorder in 20.4%. PSP-CDS scores were highest (worst) in PSP-RS; and correlated moderately with disease duration (r s  = 0.45, P < 0.001) and weakly with caregiver burden (r s  = 0.22, P = 0.029) in the overall cohort. Three of 48 (6.3%) patients who had whole-exome sequencing harboured pathogenic/likely pathogenic GBA variants., Conclusions: Significant heterogeneity in clinical features and disease burden, and high rates of RBD symptoms, visual hallucinations, and familial involvement were observed in this relatively large cohort. Our findings highlight important considerations when assessing Asian patients, and provide further support for the notion of overlapping neurobiology between PSP and Lewy body disorders., Competing Interests: Declaration of competing interest The authors have no financial conflicts of interest., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Nicotine is the most prominent psychoactive/addictive chemical substance consumed worldwide among young players in team sports. Moreover, urinary nicotine discharge and nicotine-based products disposal in environmental waters has been unavoidable in recent years. Therefore, sensitive monitoring of nicotine content in environmental waters and human urine samples is essential. In this study, we developed a miniaturized novel green, low-cost, sensitive, in-syringe-based semi-automated fast drug extraction (FaDEx) protocol coupled with gas chromatography-flame ionization detection (GC-FID) for the efficient environmental and bio-monitoring of nicotine in aqueous samples. The FaDEx method consists of two steps; firstly, the target analyte was extracted using dimethyl carbonate (a green solvent) and extraction salts. After that, the extraction solvent was passed automatically through the solid-phase extraction cartridge at a constant flow rate for the cleanup process to achieve the sensitive nicotine analysis by GC-FID. Under optimized experimental conditions, the developed method showed excellent linearity over the concentration ranges between 20-2000 ng mL -1 with a correlation coefficient >0.99. The detection and quantification limits were 4 and 20 ng mL -1 , respectively. The presented method was applied to monitor and assess nicotine exposure in sports-persons' urine and environmental water samples. The method accuracy and precision in terms of relative recovery and relative standard deviation (for triplicate analysis) were 85.4-110.2% and ≤8%, respectively. Finally, the impact of our procedure on the environment from a green analytical chemistry view was assessed using a novel metric system called AGREE, and obtained the greenness score of 0.87, indicating its an efficient alternative green analytical protocol for routine environmental and bio-monitoring of nicotine in environmental and biological samples., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Paraganglioma of the urinary bladder is a rare neuroendocrine tumor which originates from the chromaffin tissue of the sympathetic nervous system. It only accounts for about 0.05% of all vesical tumors. Bladder paraganglioma may also present with non-specific symptoms which could easily lead to misdiagnosis. In this report, emphasis on the histomorphology and immunohistochemical profile of the tumor is stressed as the morphological findings could overlap with relatively more common urothelial neoplasms. Distinction from other tumors is of utter importance because of different therapeutic options. Here, we present a case of a 52 year-old, filipino, male, previously diagnosed with colonic tubulovillous adenoma, presenting with dysuria and hematuria who, after undergoing CT Stonogram revealed an incidental finding of a lobulated mass measuring 5.7 cm located at the anteroinferior portion of the urinary bladder wall.

Background: We aimed to evaluate the effect of dignity therapy on the dignity, distress, and quality of life of terminally-ill adult patients., Methods: All randomized controlled trials published prior to Jan 2021 were searched through database, including PubMed, Medline, OVID, Cochrane Library, CINAHL, Web of Science, Scopus, ProQuest Central, KMBASE, KoreaMed, NDSL, and RISS. The RoB 2 was used to assess risk of bias. Effect sizes, Hedge's g and Higgins I 2 -statistics were used for meta-analysis., Results: We finally identified 10 studies for a systematic review, and eight studies out of them were selected for a meta-analysis. Overall, 776 participants were included in the meta-analysis. There were significant differences between with and without dignity therapy groups in dignity and anxiety (SMD = -0.3805, Cl = -0.5606, -0.2004; SMD = -0.1932, Cl = -0.3774, -0.0090, respectively) while there was no significant difference in quality of life and depression (SMD=0.4678, Cl = -0.0989, 1.0345; SMD= -0.0513, Cl= -0.2461, 0.1434, respectively)., Conclusion: Dignity therapy may be effective for terminally ill patients on dignity and anxiety. We suggested further empirical studies with dignity therapy and repetitive meta-analysis in the future due to heterogeneity of the studies., (Copyright © 2023 Lee et al. Published by Tehran University of Medical Sciences.)

Introduction: The purpose of this study was to determine whether data preprocessing and augmentation could improve visual field (VF) prediction of recurrent neural network (RNN) with multi-central datasets., Methods: This retrospective study collected data from five glaucoma services between June 2004 and January 2021. From an initial dataset of 331,691 VFs, we considered reliable VF tests with fixed intervals. Since the VF monitoring interval is very variable, we applied data augmentation using multiple sets of data for patients with more than eight VFs. We obtained 5,430 VFs from 463 patients and 13,747 VFs from 1,076 patients by setting the fixed test interval to 365 ± 60 days (D = 365) and 180 ± 60 days (D = 180), respectively. Five consecutive VFs were provided to the constructed RNN as input and the 6th VF was compared with the output of the RNN. The performance of the periodic RNN (D = 365) was compared to that of an aperiodic RNN. The performance of the RNN with 6 long- and short-term memory (LSTM) cells (D = 180) was compared with that of the RNN with 5-LSTM cells. To compare the prediction performance, the root mean square error (RMSE) and mean absolute error (MAE) of the total deviation value (TDV) were calculated as accuracy metrics., Results: The performance of the periodic model (D = 365) improved significantly over aperiodic model. Overall prediction error (MAE) was 2.56 ± 0.46 dB versus 3.26 ± 0.41 dB (periodic vs. aperiodic) (p &lt; 0.001). A higher perimetric frequency was better for predicting future VF. The overall prediction error (RMSE) was 3.15 ± 2.29 dB versus 3.42 ± 2.25 dB (D = 180 vs. D = 365). Increasing the number of input VFs improved the performance of VF prediction in D = 180 periodic model (3.15 ± 2.29 dB vs. 3.18 ± 2.34 dB, p &lt; 0.001). The 6-LSTM in the D = 180 periodic model was more robust to worsening of VF reliability and disease severity. The prediction accuracy worsened as the false-negative rate increased and the mean deviation decreased., Conclusion: Data preprocessing with augmentation improved the VF prediction of the RNN model using multi-center datasets. The periodic RNN model predicted the future VF significantly better than the aperiodic RNN model., (© 2023 The Author(s). Published by S. Karger AG, Basel.)

Background: Cardiotoxicity as a result of anthracycline chemotherapy has been linked to increased morbidity and mortality in breast cancer patients. There is a need for early detection through risk factor identification. To date, no large multicenter study has been conducted to describe the incidence, risk factors and clinical and demographic profiles of breast cancer patients with anthracycline-induced cardiotoxicity (AIC) in the Philippines., Methods: This was a nationwide multicenter retrospective cohort study among adult breast cancer patients who underwent anthracycline chemotherapy from 2015 to 2020 in 10 sites in the Philippines. Baseline characteristics and possible risk factors for AIC were retrieved from medical records and cancer registries. AIC was defined as a reduction of left ventricular ejection fraction (LVEF) by > 10% from baseline to a value of < 53% or the development of overt left ventricular systolic dysfunction or heart failure (HF). Odds ratios from logistic regression were computed to determine risk factors associated with AIC using STATA-15.0 software., Results: Out of 341 patients included, 33 had AIC, accounting for an incidence of 9.68%. Nine patients (2.6%) had clinical HF. AIC patients had a mean age of 53.91 ± 10.84 years. Breast cancer AIC patients were significantly older and had lower body mass index (BMI) than those without AIC. AIC patients had significantly more comorbidities, especially hypertension and atrial fibrillation. Multivariate analysis showed that patients with any preexisting comorbidity are approximately 12.37 times as likely to have AIC, while those with concurrent chemotherapy are 0.07 times or 93% less likely to have AIC., Conclusion: Among adult breast cancer patients undergoing anthracycline chemotherapy, we determined a high incidence of cardiotoxicity at 9.68%. Having preexisting comorbidities gave patients 12 times increased odds of developing anthracycline cardiotoxicity. The presence of concurrent non-anthracycline chemotherapy showed an inverse association with the development of AIC which we attribute largely to patient selection in a retrospective study. The significantly higher propensity for AIC development in patients with preexisting comorbidities may warrant closer monitoring and control of patient comorbidities such as hypertension among patients undergoing anthracycline chemotherapy., Competing Interests: The authors declare no potential conflict of interest., (Copyright 2022, Gerodias et al.)

Summary: Adult-onset nesidioblastosis is a rare complication of Roux-en-Y gastric bypass surgery and may occur months to years after the initial surgical procedure. It is manifested by a hyperinsulinemic, hypoglycemic state. The annual incidence of adult-onset hyperinsulinemic hypoglycemia is believed to be less than 0.1 in 1 000 000 with a mean age of onset of 47 years (1). Here, we describe a patient who presented with worsening hypoglycemic symptoms for 1 year prior to presentation that eventually progressed to hypoglycemic seizures. The onset of this hypoglycemia was 5 years after Roux-en-Y gastric bypass surgery. A full neurological evaluation, which included an EEG, head CT, and MRI, was performed to rule out epilepsy and other seizure-related disorders. After hypoglycemia was confirmed, extensive laboratory studies were obtained to elucidate the cause of the hypoglycemia and differentiate nesidioblastosis from insulinoma. Once the diagnosis of nesidioblastosis was established, a sub-total pancreatectomy was performed, and the patient was discharged and placed on acarbose, a competitive reversible inhibitor of pancreatic α-amylase and intestinal brush border α-glucosidases which slows carbohydrate absorption. The lack of information and understanding of nesidioblastosis due to its rarity makes any knowledge of this rare but important surgical complication essential. As incidence of obesity increases, the number of gastric bypasses being performed increases with it, and understanding this disease process will be essential for the primary care provider. This is the primary reason for the writing of this publication., Learning Points: Nesidioblastosis is a persistent hyperinsulinemic, hypoglycemic state, mostly seen after Roux-en-Y gastric bypass surgery, with symptoms occurring postprandially. The incidence is 0.1-0.3% of all post Roux-en-Y gastric bypass patients. The key diagnostic clue to identifying nesidioblastosis is a positive selective arterial calcium stimulation test, showing a diffuse pattern of increased basal hepatic venous insulin concentration, whereas insulinomas would show focal increases. Pathological specimen of pancreas will show diffuse hypertrophy of beta cells. Management includes acarbose and total or subtotal pancreatectomy, which can be curative. With the prevalence of obesity increasing and more patients turning to Roux-en-Y gastric bypass, more patients may be at risk of this potential surgical complication.

The numerical study was conducted to compare process performance depending on the pump type and process configuration. The daily monitoring data of seawater temperature and salinity offshore from Daesan, Republic of Korea was used to reflect the site-specific seawater conditions. An algorithm for reverse osmosis in constant permeate mode was developed to simulate the process in time-variant conditions. Two types of pumps with different maximum leachable efficiencies were employed to organize pump-train configuration: separated feed lines and common pressure center design. The results showed pump type and design configuration did not have a significant effect on process performance. The annual means of specific energy consumption ( SEC ) for every design configuration were under 2 kWh/m 3 , except for a worst-case. The worst-case was decided when the pump was operated out of the best operation range. The two operation strategies were evaluated to determine the optimal configuration. The permeate flow rate was reduced to 80% of the designed permeate flow rate with two approaches: feed flow rate reduction in every train and pump shutdown in a specific train. The operation mode with feed flow rate reduction was more efficient than the other. The operating pressure reduction led to a decrease in SEC .

Background: Corneal topography is a clinically validated examination method for keratoconus. However, there is no clear guideline regarding patient selection for corneal topography. We developed and validated a novel artificial intelligence (AI) model to identify patients who would benefit from corneal topography based on basic ophthalmologic examinations, including a survey of visual impairment, best-corrected visual acuity (BCVA) measurement, intraocular pressure (IOP) measurement, and autokeratometry., Methods: A total of five AI models (three individual models with fully connected neural network including the XGBoost, and the TabNet models, and two ensemble models with hard and soft voting methods) were trained and validated. We used three datasets collected from the records of 2,613 patients' basic ophthalmologic examinations from two institutions to train and validate the AI models. We trained the AI models using a dataset from a third medical institution to determine whether corneal topography was needed to detect keratoconus. Finally, prospective intra-validation dataset (internal test dataset) and extra-validation dataset from a different medical institution (external test dataset) were used to assess the performance of the AI models., Results: The ensemble model with soft voting method outperformed all other AI models in sensitivity when predicting which patients needed corneal topography (90.5% in internal test dataset and 96.4% in external test dataset). In the error analysis, most of the predicting error occurred within the range of the subclinical keratoconus and the suspicious D-score in the Belin-Ambrósio enhanced ectasia display. In the feature importance analysis, out of 18 features, IOP was the highest ranked feature when comparing the average value of the relative attributions of three individual AI models, followed by the difference in the value of mean corneal power., Conclusion: An AI model using the results of basic ophthalmologic examination has the potential to recommend corneal topography for keratoconus. In this AI algorithm, IOP and the difference between the two eyes, which may be undervalued clinical information, were important factors in the success of the AI model, and may be worth further reviewing in research and clinical practice for keratoconus screening., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Ahn, Kim, Chung, Kim, Jun, Kim and Seo.)

Purpose: Air monitoring has been the accepted exposure assessment of toxic metals from, e.g., welding, but a method characterizing the actual dose delivered to the lungs would be preferable. Sampling of particles in exhaled breath can be used for the biomonitoring of both endogenous biomarkers and markers of exposure. We have explored a new method for the sampling of metals in exhaled breath from the small airways in a study on welders., Methods: Our method for particle sampling, Particles in Exhaled Air (PExA®), is based on particle counting and inertial impaction. We applied it on 19 stainless steel welders before and after a workday. In parallel, air monitoring of chromium, manganese and nickel was performed as well as blood sampling after work., Results: Despite substantial exposure to welding fumes, we were unable to show any significant change in the metal content of exhaled particles after, compared with before, exposure. However, the significance might be obscured by a substantial analytical background noise, due to metal background in the sampling media and possible contamination during sampling, as an increase in the median metal contents were indicated., Conclusions: If efforts to reduce background and contamination are successful, the PExA® method could be an important tool in the investigations of metals in exhaled breath, as the method collects particles from the small airways in contrast to other methods. In this paper, we discuss the discrepancy between our findings and results from studies, using the exhaled breath condensate (EBC) methodology., (© 2022. The Author(s).)

Phloretin is one of the apple polyphenols with anticancer activities. Since tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) serves important roles in inducing apoptosis, the present study examined the effect of phloretin on TRAIL-induced apoptosis in colon cancer cells. Treatment with both phloretin and TRAIL markedly suppressed the survival of cancer cells from several colon cancer cell lines compared with that of cells treated with either TRAIL or phloretin. Additionally, decreased numbers of colonies were observed following addition of phloretin and TRAIL. Furthermore, TRAIL- and phloretin-treated HT-29-Luc cells exhibited decreased luciferase activity. Increased apoptosis was observed in phloretin- and TRAIL-treated HT-29-Luc colon cancer cells, accompanying elevated levels of cleaved poly(ADP-ribose) polymerase, and caspase-3, -8 and -9. The expression levels of MCL1 apoptosis regulator BCL2 family member (Mcl-1) were decreased following addition of phloretin in colon cancer cells. In addition, overexpression of Mcl-1 in phloretin- and TRAIL-treated HT-29-Luc cells resulted in increased cell survival. Treatment of HT-29-Luc cells with a combination of cycloheximide (CHX) and phloretin led to a more prominent decrease in Mcl-1 expression compared with that in cells treated with CHX alone, while Mcl-1 expression was recovered by treatment with MG132. Binding of ubiquitin with Mcl-1 was verified using immunoprecipitation. Intraperitoneal injection of both TRAIL and phloretin into tumor xenografts was associated with a decreased tumor volume compared with that following injection with either TRAIL or phloretin. Overall, the present results suggest a synergistic effect of phloretin on TRAIL-induced apoptosis in colon cancer cells., Competing Interests: The authors declare that they have no competing interests., (Copyright: © Kim et al.)

At the start of the COVID-19 pandemic, there was an increase in the use of antibiotics for the treatment of community-acquired respiratory tract infection (CA-ARI) in patients admitted for suspected or confirmed COVID-19, raising concerns for misuse. These antibiotics are not under the usual purview of the antimicrobial stewardship unit (ASU). Serum procalcitonin, a biomarker to distinguish viral from bacterial infections, can be used to guide antibiotic recommendations in suspected lower respiratory tract infection. We modified our stewardship approach, and used a procalcitonin-guided strategy to identify “high yield” interventions for audits in patients admitted with CA-ARI. With this approach, there was an increase in the proportion of patients with antibiotics discontinued within 4 days (16.5% vs. 34.9%, p < 0.001), and the overall duration of antibiotic therapy was significantly shorter [7 (6−8) vs. 6 (3−8) days, p < 0.001]. There was a significant decrease in patients with intravenous-to-oral switch of antibiotics to “complete the course” (45.3% vs. 34.4%, p < 0.05). Of the patients who had antibiotics discontinued, none were restarted on antibiotics within 48 h, and there was no-30-day readmission or 30-day mortality attributed to respiratory infection. This study illustrates the importance of the antimicrobial stewardship during the pandemic and the need for ASU to remain attuned to prescriber’s practices, and adapt accordingly to address antibiotic misuse to curb antimicrobial resistance.

Our team has previously reported a series of quinazoline-based lapatinib hybrids as potent kinase-targeting anticancer agents. Among them, AF8c showed a relatively safe profile in colorectal cancer (CRC) cells. In this study, we delineate a novel anticancer activity of AF8c in CRC cells. AF8c mediated p53-dependent apoptosis of CRC cells via the generation of endoplasmic reticulum (ER) stress and reactive oxygen species (ROS), as well as activation of nuclear respiratory factor 2 alpha subunit (Nrf2) and death receptor 5 (DR5), among others. The silencing of DR5 attenuated the expression levels of Nrf2 and partially inhibited AF8c-induced apoptosis. Additionally, upregulation of Nrf2 by AF8c evoked apoptosis through a decrease in antioxidant levels. Treatment of a CRC mice model with AF8c also resulted in the upregulation of DR5, Nrf2, and CHOP proteins, subsequently leading to a significant decrease in tumor burden. In comparison with lapatinib, AF8c showed higher cellular antiproliferative activity at the tested concentrations in CRC cells and synergized TRAIL effects in CRC cells. Overall, our results suggest that AF8c-induced apoptosis may be associated with DR5/Nrf2 activation through ER stress and ROS generation in CRC cells. These findings indicate that AF8c represents a promising polypharmacological molecule for the treatment of human CRC.

We report a clinical case of mentally challenged young gentleman who was repeatedly hospitalized for respiratory symptoms. Contrast-enhanced CT (computed tomography) thorax revealed tree-in-bud (TIB) opacities. Provisional diagnosis of pulmonary tuberculosis was made and was referred to the respiratory team. However, after listening to patient's voice and reviewing the images on CT thorax, the diagnosis was confirmed as aspiration bronchiolitis.

Background: Human papillomavirus (HPV) vaccination is a form of primary prevention for cervical cancer. The HPV vaccination rate of female university students is not high in Korea and China. Therefore, the purpose of this study was to identify and compare the factors associated with intention to receive HPV vaccination between Korean and Chinese female university students., Methods: The participants were 273 Korean and 317 Chinese female university students who had not been vaccinated for HPV, and data were collected using a self-reported questionnaire about attitudes toward HPV vaccination, HPV knowledge, perceptions of HPV infection, and intention to receive HPV vaccine., Results: There were no significant differences between the Korean and Chinese female university students in HPV knowledge, attitudes, perceptions, and vaccination intention. The factors influencing the intention of HPV vaccination in Korean students were a positive attitude toward the HPV vaccine and a high HPV knowledge score. For Chinese students, sexual experience, awareness of genital warts, a positive attitude toward the HPV vaccine, a high HPV knowledge scores, a perception of the seriousness of HPV infection, and negative emotions regarding HPV infection were significant factors., Conclusions: It is important to improve attitudes and knowledge about HPV and the HPV vaccine in order to enhance HPV vaccination both in Korea and China. Perceived seriousness and negative emotions regarding HPV infection should be used as a framework to develop subject-tailored interventions in China., (© 2022. The Author(s).)

A 62-year-old man presented with acute abdominal and flank pain, oligoanuria and severe acute kidney injury. Unenhanced CT imaging did not detect urolithiasis or hydronephrosis. There was an early blood pressure surge followed by an intense inflammatory response, with a rise in peripheral blood leucocytes and C reactive protein. His urinalysis was bland but the serum lactate dehydrogenase was markedly elevated. CT angiograms demonstrated multiple pulmonary emboli and bilateral renal artery thromboembolism, with occlusion of the left main renal artery. Despite an 88-hour delay from pain onset, catheter-directed thrombolysis and thromboaspiration of both renal arteries were successfully performed, allowing the patient to recover enough kidney function to cease haemodialysis. A patent foramen ovale with right-to-left shunting was discovered, and paradoxical embolism was suspected as the cause of renal infarction. The benefit of catheter-directed reperfusion after prolonged bilateral renal ischaemia is not easily predicted by the severity or duration of acute kidney injury alone., Competing Interests: Competing interests: None declared., (© BMJ Publishing Group Limited 2022. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Diagnosing Clostridioides difficile infection (CDI) is complicated. There have been reports on effects of compliance with anti-C. difficile prescription guidelines on patient outcomes. However, the causes of non-adherence and their impact on outcomes have rarely been explored. Therefore, an investigation on the risk factors for non-adherence with treatment guidelines and their influence on recurrence is important., Methods: This case-control study was conducted with patients with a positive C. difficile culture from March 2020 to April 2021. We conducted analysis based on treatment categories using factors associated with recurrent CDI as variables. Univariate and multivariable analyses were conducted to identify risk factors for non-adherence with treatment guidelines., Results: In total, culture positive stool samples from 172 patients were analyzed. Having positive glutamate dehydrogenase antigen (GDH Ag), negative toxin enzyme immunoassay (EIA), and positive nucleic acid amplification test (NAAT) (GDH+/toxin EIA-/NAAT +) results were associated with both under- (adjusted odds ratio [aOR] 3.49 [95% CI 1.62-7.51], p = 0.001) and over-treatment (aOR 0.17 [95% CI 0.06-0.48], p = 0.001). Patients with refractory diarrhea were over treated (aOR 2.71 [95% CI 1.02-7.20], p = 0.046). Patients with an increased risk of CDI recurrence were not over treated., Conclusions: Our results suggest that non-adherence with CDI treatment guidelines depends on the duration of symptoms and rapid EIA test results. Patients with an increased risk of recurrence were neglected., (© 2022. The Author(s).)